PMID- 36761918
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231112
IS  - 1664-2295 (Print)
IS  - 1664-2295 (Electronic)
IS  - 1664-2295 (Linking)
VI  - 13
DP  - 2022
TI  - Therapeutic potential of blocking GAPDH nitrosylation with CGP3466b in 
      experimental autoimmune encephalomyelitis.
PG  - 979659
LID - 10.3389/fneur.2022.979659 [doi]
LID - 979659
AB  - Multiple sclerosis (MS) is a neuroinflammatory disease of the central nervous 
      system (CNS). Although classically considered a demyelinating disease, 
      neuroaxonal injury occurs in both the acute and chronic phases and represents a 
      pathologic substrate of disability not targeted by current therapies. Nitric 
      oxide (NO) generated by CNS macrophages and microglia contributes to neuroaxonal 
      injury in all phases of MS, but candidate therapies that prevent NO-mediated 
      injury have not been identified. Here, we demonstrate that the multifunctional 
      protein glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is robustly nitrosylated 
      in the CNS in the experimental autoimmune encephalomyelitis (EAE) mouse model of 
      MS. GAPDH nitrosylation is blocked in vivo with daily administration of CGP3466b, 
      a CNS-penetrant compound with an established safety profile in humans. Consistent 
      with the known role of nitrosylated GAPDH (SNO-GAPDH) in neuronal cell death, 
      blockade of SNO-GAPDH with CGP3466b attenuates neurologic disability and reduces 
      axonal injury in EAE independent of effects on the immune system. Our findings 
      suggest that SNO-GAPDH contributes to neuroaxonal injury during neuroinflammation 
      and identify CGP3466b as a candidate neuroprotective therapy in MS.
CI  - Copyright (c) 2023 Godfrey, Hwang, Cho, Shanmukha, Gharibani, Abramson and 
      Kornberg.
FAU - Godfrey, Wesley H
AU  - Godfrey WH
AD  - Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, United 
      States.
FAU - Hwang, Soonmyung
AU  - Hwang S
AD  - Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, United 
      States.
FAU - Cho, Kaho
AU  - Cho K
AD  - Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, United 
      States.
FAU - Shanmukha, Shruthi
AU  - Shanmukha S
AD  - Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of 
      Medicine, Baltimore, MD, United States.
FAU - Gharibani, Payam
AU  - Gharibani P
AD  - Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, United 
      States.
FAU - Abramson, Efrat
AU  - Abramson E
AD  - Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, United 
      States.
FAU - Kornberg, Michael Davin
AU  - Kornberg MD
AD  - Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, United 
      States.
LA  - eng
GR  - K08 NS104266/NS/NINDS NIH HHS/United States
GR  - T32 GM136577/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20230124
PL  - Switzerland
TA  - Front Neurol
JT  - Frontiers in neurology
JID - 101546899
PMC - PMC9902867
OTO - NOTNLM
OT  - GAPDH
OT  - experimental autoimmune encephalomyelitis
OT  - multiple sclerosis
OT  - neuroinflammation
OT  - neuroprotection
OT  - nitric oxide
OT  - nitrosylation
COIS- MK has received consulting fees from Biogen Idec, Genentech, Janssen 
      Pharmaceuticals, Novartis, OptumRx, and TG Therapeutics on topics unrelated to 
      this manuscript. The remaining authors declare that the research was conducted in 
      the absence of any commercial or financial relationships that could be construed 
      as a potential conflict of interest.
EDAT- 2023/02/11 06:00
MHDA- 2023/02/11 06:01
PMCR- 2023/01/24
CRDT- 2023/02/10 03:15
PHST- 2022/06/27 00:00 [received]
PHST- 2022/12/30 00:00 [accepted]
PHST- 2023/02/10 03:15 [entrez]
PHST- 2023/02/11 06:00 [pubmed]
PHST- 2023/02/11 06:01 [medline]
PHST- 2023/01/24 00:00 [pmc-release]
AID - 10.3389/fneur.2022.979659 [doi]
PST - epublish
SO  - Front Neurol. 2023 Jan 24;13:979659. doi: 10.3389/fneur.2022.979659. eCollection 
      2022.